The over riding theme of the Program Project entitled "Anatomic, Physiologic and Cognitive Pathology of AD" is two fold: 1. The elucidation of the pathophysiological mechanism(s) underlying the progression of cognitive decline in the elderly and 2) the imaging of structural and functional brain abnormalities that underlie cognitive decline and define those at risk of developing AD. The emphasis in this application is to understand events and mechanisms that define the transition not only from mild cognitive impairment (MCI) to Alzheimer's disease (AD), but also the transition from healthy aging to MCI. This new emphasis will allow the program to investigate the progression of cognitive decline all the way from behavioral and in vivo anatomical perspectives (i.e., structural and functional imaging) to cell and molecular biological levels. The program brings together a number of basic scientists and clinicians from two major Chicago-area medical schools, namely Rush University Medical Center and Northwestern University Medical School. Colleagues from Stanford University and the Nathan Klein Institute of New York University are also participating. The project will be based at the Rush University Medical Center. The proposed Program Project consists of Administrative and Statistics and Data Management Cores in addition to the following four research projects: 1. In vivo Detection of the Anatomic and Functional Progression of AD (Leyla deToledo- Morrell, PI), 2. fMRI Analysis of Medial Temporal Lobe Function in Aging and AD (John Gabrieli and Glenn Stebbins, Pis), 3. Galanin Remodeling in the Progression of Alzheimer's Disease (Elliot Mufson, PI) and 4. Tau Truncation and Conformation in AD Progression (Lester Binder, PI). Each core will support all four of these research projects. A major strength of the proposed research is that all the projects will use well characterized participants (or brain tissue from participants) who will be followed clinically with yearly evaluations.